Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of the MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFß mRNA upregulation, as well as invasion. Moreover, the cleavage under targets and release using nuclease (CUT&RUN) assay coupled with next-generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor regions of genes encoding TGFß and its signaling pathway members in cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1 and this study offers new therapeutic strategies to treat Bcl-xL-overexpressing cancer.

Chromatin remodeling-driven autophagy activation induces cisplatin resistance in oral squamous cell carcinoma.

It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.

Optimizing the Amino Acid Sequence Enhances the Productivity and Bioefficacy of the RBP-Albumin Fusion Protein.

The significant growth of the global protein drug market, including fusion proteins, emphasizes the crucial role of optimizing amino acid sequences to enhance the productivity and bioefficacy. Among these fusion proteins, RBP-IIIA-IB, comprising retinol-binding protein in conjunction with the albumin domains, IIIA and IB, has displayed efficacy in alleviating liver fibrosis by inhibiting the activation of hepatic stellate cells (HSCs). This study aimed to address the issue of the low productivity in RBP-IIIA-IB. To induce structural changes, the linking sequence, EVDD, between domain IIIA and IB in RBP-IIIA-IB was modified to DGPG, AAAA, and GGPA. Among these, RBP-IIIA-AAAA-IB demonstrated an increase in yield (>4-fold) and a heightened inhibition of HSC activation. Furthermore, we identified amino acid residues that could form disulfide bonds when substituted with cysteine. Through the mutation of N453S-V480S in RBP-IIIA-AAAA-IB, the productivity further increased by over 9-fold, accompanied by an increase in anti-fibrotic activity. Overall, there was a more than 30-fold increase in the fusion protein's yield. These findings demonstrate the effectiveness of modifying linker sequences and introducing extra disulfide bonds to improve both the production yield and biological efficacy of fusion proteins.

Contrast-free dynamic susceptibility contrast using sinusoidal and bolus oxygenation challenges.

Deoxygenation-based dynamic susceptibility contrast (dDSC) MRI uses respiratory challenges as a source of endogenous contrast as an alternative to gadolinium injection. These gas challenges induce T2*-weighted MRI signal losses, after which tracer kinetics modeling was applied to calculate cerebral perfusion. This work compares three gas challenges, desaturation (transient hypoxia), resaturation (transient normoxia), and SineO2 (sinusoidal modulation of end-tidal oxygen pressures) in a cohort of 10 healthy volunteers (age 37 ± 11 years; 60% female). Perfusion estimates consisted of cerebral blood flow (CBF), cerebral blood volume (CBV), and mean transit time (MTT). Calculations were computed using a traditional tracer kinetics model in the time domain for desaturation and resaturation and in the frequency domain for SineO2. High correlations and limits of agreement were observed among the three deoxygenation-based paradigms for CBV, although MTT and CBF estimates varied with the hypoxic stimulus. Cross-modality correlation with gadolinium DSC was lower, particularly for MTT, but on a par with agreement between the other perfusion references. Overall, this work demonstrated the feasibility and reliability of oxygen respiratory challenges to measure brain perfusion. Additional work is needed to assess the utility of dDSC in the diagnostic evaluation of various pathologies such as ischemic strokes, brain tumors, and neurodegenerative diseases.

Differential effect of cancer-associated fibroblast-derived extracellular vesicles on cisplatin resistance in oral squamous cell carcinoma via miR-876-3p.

Rationale: Platinum-based chemotherapy is commonly used for treating solid tumors, but drug resistance often limits its effectiveness. Cancer-associated fibroblast (CAF)-derived extracellular vesicle (EV), which carry various miRNAs, have been implicated in chemotherapy resistance. However, the molecular mechanism through which CAFs modulate cisplatin resistance in oral squamous cell carcinoma (OSCC) is not well understood. We employed two distinct primary CAF types with differential impacts on cancer progression: CAF-P, representing a more aggressive cancer-promoting category, and CAF-D, characterized by properties that moderately delay cancer progression. Consequently, we sought to investigate whether the two CAF types differentially affect cisplatin sensitivity and the underlying molecular mechanism. Methods: The secretion profile was examined by utilizing an antibody microarray with conditioned medium obtained from the co-culture of OSCC cells and two types of primary CAFs. The effect of CAF-dependent factors on cisplatin resistance was investigated by utilizing conditioned media (CM) and extracellular vesicle (EVs) derived from CAFs. The impacts of candidate genes were confirmed using gain- and loss-of-function analyses in spheroids and organoids, and a mouse xenograft. Lastly, we compared the expression pattern of the candidate genes in tissues from OSCC patients exhibiting different responses to cisplatin. Results: When OSCC cells were cultured with conditioned media (CM) from the two different CAF groups, cisplatin resistance increased only under CAF-P CM. OSCC cells specifically expressed insulin-like growth factor binding protein 3 (IGFBP3) after co-culture with CAF-D. Meanwhile, IGFBP3-knockdown OSCC cells acquired cisplatin resistance in CAF-D CM. IGFBP3 expression was promoted by GATA-binding protein 1 (GATA1), a transcription factor targeted by miR-876-3p, which was enriched only in CAF-P-derived EV. Treatment with CAF-P EV carrying miR-876-3p antagomir decreased cisplatin resistance compared to control miRNA-carrying CAF-P EV. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, there was a positive correlation between IGFBP3 and GATA1 expression and cisplatin sensitivity in OSCC tissues from patients. Conclusion: These results provide insights for overcoming cisplatin resistance, especially concerning EVs within the tumor microenvironment. Furthermore, it is anticipated that the expression levels of GATA1 and miR-876-3p, along with IGFBP3, could aid in the prediction of cisplatin resistance.

3D simulation of interosseous interference in sagittal split ramus osteotomy for mandibular asymmetry.

BACKGROUND: The purpose of this study was to evaluate the pattern of predicted interosseous interference and to determine the influencing factor to volume of bony interference using a computer-assisted simulation system. This retrospective study recruited 116 patients with mandibular prognathism who had undergone sagittal split ramus osteotomy (SSRO) with or without maxillary osteotomy. The patients were divided into 3 groups according to the amount of menton (Me) deviation: less than 2 mm (Group 1), 2-4 mm (Group 2), and more than 4 mm (Group 3). Changes in the distal segments following BSSRO and the volume of the interosseous interference between the proximal and distal segments were simulated after matching preoperative occlusion and postoperative expected occlusion with the cone-beam computed tomography data. Ramal inclinations and other skeletal measurements were analyzed before surgery, immediately after surgery, and at least 6 months after surgery. RESULTS: The anticipated interosseous interference was more frequently noted on the contralateral side of chin deviation (long side) than the deviated site (short side) in Groups 2 and 3. More interference volume was predicted at the long side (186 ± 343.9 mm3) rather than the short side (54.4 ± 124.4 mm3) in Group 3 (p = 0.033). The bilateral difference in the volume of the interosseous interference of the osteotomized mandible was significantly correlated with the Me deviation (r = - 0.257, p = 0.009) and bilateral ramal inclination (r = 0.361, p < 0.001). The predictor variable that affected the volume of the osseous interference at each side was the amount of Me deviation (p = 0.010). CONCLUSION: By using the 3D simulation system, the potential site of bony collision could be visualized and successfully reduced intraoperatively. Since the osseous interference can be existed on any side, unilaterally or bilaterally, 3D surgical simulation is necessary before surgery to predict the osseous interference and improve the ramal inclination.

Bcl-xL is translocated to the nucleus via CtBP2 to epigenetically promote metastasis.

Besides its mitochondria-based anti-apoptotic role, Bcl-xL also travels to the nucleus to promote cancer metastasis by upregulating global histone H3 trimethyl Lys4 (H3K4me3) and TGFß transcription. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates H3K4me3 modification are not understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced cell migration and metastasis in mouse models. Furthermore, knockout of CtBP2 suppresses Bcl-xL transcription. The binding between Bcl-xL and CtBP2 is required for their interaction with MLL1, a histone H3K4 methyltransferase. Pharmacologic inhibition of MLL1 enzymatic activity reverses Bcl-xL-induced H3K4me3 and TGFß mRNA upregulation as well as cell invasion. Moreover, cleavage under targets and release using nuclease (CUT&RUN) coupled with next generation sequencing reveals that H3K4me3 modifications are particularly enriched in the promotor region of genes encoding TGFß and its signaling pathway in the cancer cells overexpressing Bcl-xL. Altogether, the metastatic function of Bcl-xL is mediated by its interaction with CtBP2 and MLL1.

Atypical lipomatous tumour/well-differentiated liposarcoma found in the buccal mucosa: A rare case report.

Oral liposarcomas are uncommon diseases, the most predominant histopathological subtype being atypical lipomatous tumour/well-differentiated liposarcoma. In regard to its clinical aspects in the oral cavity, it is challenging to confirm a diagnosis and develop a treatment plan. In this case report, we present a rare case of atypical lipomatous tumour/well-differentiated liposarcoma in the right cheek of a 77-year-old male patient. Conservative surgery was performed considering the histopathological subtype of the neoplasm. Knowledge of the clinical and histopathological characteristics of this rare disease is essential to maintaining function and aesthetics through conservative treatment in older patients.

An Fc variant with two mutations confers prolonged serum half-life and enhanced effector functions on IgG antibodies.

The pH-selective interaction between the immunoglobulin G (IgG) fragment crystallizable region (Fc region) and the neonatal Fc receptor (FcRn) is critical for prolonging the circulating half-lives of IgG molecules through intracellular trafficking and recycling. By using directed evolution, we successfully identified Fc mutations that improve the pH-dependent binding of human FcRn and prolong the serum persistence of a model IgG antibody and an Fc-fusion protein. Strikingly, trastuzumab-PFc29 and aflibercept-PFc29, a model therapeutic IgG antibody and an Fc-fusion protein, respectively, when combined with our engineered Fc (Q311R/M428L), both exhibited significantly higher serum half-lives in human FcRn transgenic mice than their counterparts with wild-type Fc. Moreover, in a cynomolgus monkey model, trastuzumab-PFc29 displayed a superior pharmacokinetic profile to that of both trastuzumab-YTE and trastuzumab-LS, which contain the well-validated serum half-life extension Fcs YTE (M252Y/S254T/T256E) and LS (M428L/N434S), respectively. Furthermore, the introduction of two identified mutations of PFc29 (Q311R/M428L) into the model antibodies enhanced both complement-dependent cytotoxicity and antibody-dependent cell-mediated cytotoxicity activity, which are triggered by the association between IgG Fc and Fc binding ligands and are critical for clearing cancer cells. In addition, the effector functions could be turned off by combining the two mutations of PFc29 with effector function-silencing mutations, but the antibodies maintained their excellent pH-dependent human FcRn binding profile. We expect our Fc variants to be an excellent tool for enhancing the pharmacokinetic profiles and potencies of various therapeutic antibodies and Fc-fusion proteins.

Anti-PTK7 Monoclonal Antibodies Exhibit Anti-Tumor Activity at the Cellular Level and in Mouse Xenograft Models of Esophageal Squamous Cell Carcinoma.

PTK7 is a catalytically defective receptor protein tyrosine kinase upregulated in various cancers, including esophageal squamous cell carcinoma (ESCC). In previous studies, we observed a positive correlation between PTK7 expression levels and tumorigenicity in various ESCC cell lines and xenograft mice with ESCC KYSE-30 cells. In this study, we analyzed the effects of anti-PTK7 monoclonal antibodies (mAbs) on the tumorigenic activity in KYSE-30 cells and in mouse xenograft models. PTK7 mAb-32 and mAb-43 bind with a high affinity to the extracellular domain of PTK7. PTK7 mAbs significantly reduced three-dimensional cell proliferation, adhesion, wound healing, and migration. PTK7 mAbs also reduce chemotactic invasiveness by decreasing MMP-9 secretion. PTK7 mAbs decreased actin cytoskeleton levels in the cortical region of KYSE-30 cells. PTK7 mAbs reduced the phosphorylation of ERK, SRC, and FAK. In a mouse xenograft model of ESCC using KYSE-30 cells, PTK7 mAbs reduced tumor growth in terms of volume, weight, and the number of Ki-67-positive cells. These results demonstrated that PTK7 mAbs can inhibit the tumorigenicity of ESCC at the cellular level and in vivo by blocking the function of PTK7. Considering the anticancer activities of PTK7 mAbs, we propose that PTK7 mAbs can be used in an effective treatment strategy for PTK7-positive malignancies, such as ESCC.

Gut microbiota profiling in aged dogs after feeding pet food contained Hericium erinaceus.

Health concern of dogs is the most important issue for pet owners. People who have companied the dogs long-term provide the utmost cares for their well-being and healthy life. Recently, it was revealed that the population and types of gut microbiota affect the metabolism and immunity of the host. However, there is little information on the gut microbiome of dogs. Hericium erinaceus (H. erinaceus; HE) is one of the well-known medicinal mushrooms and has multiple bioactive components including polyphenol, ß-glucan, polysaccharides, ergothioneine, hericerin, erinacines, etc. Here we tested a pet food that contained H. erinaceus for improvement in the gut microbiota environment of aged dogs. A total of 18 dogs, each 11 years old, were utilized. For sixteen weeks, the dogs were fed with 0.4 g of H. erinaceus (HE-L), or 0.8 g (HE-H), or without H. erinaceus (CON) per body weight (kg) with daily diets (n = 6 per group). Taxonomic analysis was performed using metagenomics to investigate the difference in the gut microbiome. Resulting from principal coordinates analysis (PCoA) to confirm the distance difference between the groups, there was a significant difference between HE-H and CON due to weighted Unique fraction metric (Unifrac) distance (p = 0.047), but HE-L did not have a statistical difference compared to that of CON. Additionally, the result of Linear discriminate analysis of effect size (LEfSe) showed that phylum Bacteroidetes in HE-H and its order Bacteroidales increased, compared to that of CON, Additionally, phylum Firmicutes in HE-H, and its genera (Streptococcus, Tyzzerella) were reduced. Furthermore, at the family level, Campylobacteraceae and its genus Campylobacter in HE-H was decreased compared to that of CON. Summarily, our data demonstrated that the intake of H. erinaceus can regulate the gut microbial community in aged dogs, and an adequate supply of HE on pet diets would possibly improve immunity and anti-obesity on gut-microbiota in dogs.

Analysis of the fluid contents of simple bone cyst in the mandible.

Description of simple bone cyst (SBC) content has been controversial. This study aimed to assess and give a clearer picture of the SBC cavity contents. Between 2014 and 2016, 19 patients with SBC verified by histopathological examination were included in this study. SBC cavity content was investigated using clinical, radiographic, surgical, and laboratory findings. The difference in components among cavity fluid, blood, and serum was evaluated using a paired sample t-test for statistical analysis. All 19 SBC cases radiographically and surgically revealed a fluid-filled cavity. The patients' average age was 21.3 ± 13.2 years, with no sex predominance found. SBCs were found mostly in the anterior mandible (n = 12, 63.2%). All lesions were filled with clear straw-colored or blood-colored floods with low concentration. Although the fluid components were similar to those in the blood and serum in the laboratory analysis, the statistical analysis revealed that the fluid components were not significantly different only for eosinophil (p = 0.43) and basophil (p = 0.06) counts as blood components and sodium (p = 0.76), potassium (p = 0.08), and chloride (p = 0.13) concentration as serum components. The results show that SBC is a fluid-filled cavity, with the cavity fluid being more likely similar to serum rather than blood regarding internal components.

Giant lipoma of the tongue: A case report and review of the literature.

This report presents the case of a 49-year-old man who presented with giant masses that had recently grown on the bilateral sides of the tongue. A clinical examination revealed rubbery yellowish lesions protruding from the tongue. A panoramic radiograph showed an enlarged soft tissue shadow of the tongue. Computed tomography showed well-defined circumscribed mass exhibiting a homogeneous low density on the bilateral sides of the tongue. On magnetic resonance images, the masses showed a high signal intensity on T1-weighted images and iso-signal intensity with partially hyperintense margin on fat-suppressed T2-weighted images. Surgical excision was performed, and a histopathologic examination confirmed the diagnosis of lipoma. The patient recovered well with no sign of recurrence. A giant lipoma is defined as a lipoma larger than 5 cm in diameter. A literature review of giant lipomas of the tongue is also presented herein.

Therapeutic effects of TM4SF5-targeting chimeric and humanized monoclonal antibodies in hepatocellular and colon cancer models.

The transmembrane 4 L six family member 5 (TM4SF5) is aberrantly expressed in hepatocellular and colorectal cancers, and has been implicated in tumor progression, suggesting that it could serve as a novel therapeutic target. Previously, we screened a murine antibody phage-display library to generate a novel monoclonal antibody, Ab27, that is specific to the extracellular loop 2 of TM4SF5. In this study, we evaluated the effects of chimeric Ab27 using cancer cells expressing endogenous TM4SF5 or stably overexpressing TM4SF5 in vivo and in vitro. Monotherapy with Ab27 significantly decreased tumor growth in liver and colon cancer xenograft models, including a sorafenib-resistant model, and decreased the phosphorylation of focal adhesion kinase (FAK), p27Kip1, and signal transducer and activator of transcription 3 (STAT3). No general Ab27 toxicity was observed in vivo. Combination treatment with Ab27 and sorafenib or doxorubicin exerted higher antitumor activity than monotherapy. In addition, we humanized the Ab27 sequence by the complementarity-determining region (CDR) grafting method. The humanized antibody Ab27-hz9 had reduced immunogenicity but exhibited target recognition and antitumor activity comparable with those of Ab27. Both Ab27 and Ab27-hz9 efficiently targeted tumor cells expressing TM4SF5 in vivo. These observations strongly support the further development of Ab27-hz9 as a novel therapeutic agent against liver and colorectal cancers.

Withaferin A mitigates metastatic traits in human oral squamous cell carcinoma caused by aberrant claudin-1 expression.

Abnormal expression of claudin-1 (CLDN1) has important roles in carcinogenesis and metastasis in various cancers. The role of CLDN1 in human oral squamous cell carcinoma (OSCC) remains unknown. Here, we report the functional role of CLDN1 in metastasis of human OSCC, as a potential target regulated by withaferin A. From gene expression profiling with microarray technology, we found that the majority of notable differentially expressed genes were classified into migration/invasion category. Withaferin A impaired the motility of human OSCC cells in vitro and suppressed metastatic nodule formation in an in vivo metastasis model, both associated with reduced CLDN1. CLDN1 overexpression enhanced metastatic nodule formation in vivo, resulting in severe metastatic lesions in lung tissue. Moreover, CLDN1 expression was positively correlated to lymphatic metastasis in OSCC patients. The impaired motility of human OSCC cells upon withaferin A treatment was restored by CLDN1 overexpression. Furthermore, upregulation of let-7a induced by withaferin A was inversely correlated to CLDN1 expression. Overall, these give us an insight into the function of CLDN1 for prognosis and treatment of human OSCC, substantiating further investigation into the use of withaferin A as good anti-metastatic drug candidate.

Facilitating Reparative Dentin Formation Using Apigenin Local Delivery in the Exposed Pulp Cavity.

Apigenin, a natural product belonging to the flavone class, affects various cell physiologies, such as cell signaling, inflammation, proliferation, migration, and protease production. In this study, apigenin was applied to mouse molar pulp after mechanically pulpal exposure to examine the detailed function of apigenin in regulating pulpal inflammation and tertiary dentin formation. In vitro cell cultivation using human dental pulp stem cells (hDPSCs) and in vivo mice model experiments were employed to examine the effect of apigenin in the pulp and dentin regeneration. In vitro cultivation of hDPSCs with apigenin treatment upregulated bone morphogenetic protein (BMP)- and osteogenesis-related signaling molecules such as BMP2, BMP4, BMP7, bone sialoprotein (BSP), runt-related transcription factor 2 (RUNX2), and osteocalcin (OCN) after 14 days. After apigenin local delivery in the mice pulpal cavity, histology and cellular physiology, such as the modulation of inflammation and differentiation, were examined using histology and immunostainings. Apigenin-treated specimens showed period-altered immunolocalization patterns of tumor necrosis factor (TNF)-α, myeloperoxidase (MPO), NESTIN, and transforming growth factor (TGF)-ß1 at 3 and 5 days. Moreover, the apigenin-treated group showed a facilitated dentin-bridge formation with few irregular tubules after 42 days from pulpal cavity preparation. Micro-CT images confirmed obvious dentin-bridge structures in the apigenin-treated specimens compared with the control. Apigenin facilitated the reparative dentin formation through the modulation of inflammation and the activation of signaling regulations. Therefore, apigenin would be a potential therapeutic agent for regenerating dentin in exposed pulp caused by dental caries and traumatic injury.

Chimeric Antigen Receptor T Cells With Modified Interleukin-13 Preferentially Recognize IL13Rα2 and Suppress Malignant Glioma: A Preclinical Study.

Background: Interleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells. Methods: IL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells. Results: Binding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2-) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300). Conclusion: This preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood-brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.

Experience of patients diagnosed as asymptomatic COVID-19 after dental treatment.

BACKGROUND: The potential risk of coronavirus disease 2019 (COVID-19) transmission from asymptomatic COVID-19 patients is a concern in dental practice. However, the impact of this risk is not well documented to date. This report describes our dental clinical experience with patients who did not exhibit symptoms of COVID-19 but were later confirmed as positive for COVID-19. CASE PRESENTATION: Of the 149,149 patients who visited the outpatient clinic of KNUDH and the 3291 patients who visited the Oral and Maxillofacial Surgery Clinic of KNUH, 3 were later confirmed as having COVID-1 between 1 February 2020 and 28 February 2021. Owing to close contact with these patients during their treatments, 46 dental and medical staff had to undergo quarantine from the date of the patients' confirmation of COVID-19 infection. CONCLUSION: The presented cases showed the potential existence of asymptomatic COVID-19 patients after dental treatment with aerosol-generating procedures. Clinicians should be aware of the infection prevention measures and try to protect healthcare personnel from secondary infection of COVID-19 during dental treatments.